1. Field of the Invention
The present invention relates to a process for producing enantiomerically enriched beta-amino acid derivatives which are important chiral building blocks and intermediates in pharmaceuticals. More specifically, the invention pertains to a novel process for practically, conveniently and economically producing enantiomerically enriched beta-amino acid derivatives which are useful for the synthesis of amide inhibitors of dipeptidyl peptidase-IV, which have been used to treat Type 2 diabetes.
2. Description of Related Art
The present invention provides a process for producing enantiomerically enriched beta-amino acid derivatives represented by the following general structural formula I, or its corresponding pharmaceutically acceptable salts, having the R-configuration at the stereogenic center marked with an *;

wherein Ar is phenyl, which is unsubstituted or substituted with one to five substituents independently selected from halogen, trifluoromethyl and trifluoromethoxy; Z is OR1, SR1 and NR1R2; and P is R3, OR3, and NR3R4;
R1 and R2 are each independently H, C1-8 alkyl, C5-12 cycloalkyl, aryl, or aryl-C1-2 alkyl; or R1 and R2 together with the nitrogen atom to which they are attached form a C4-7 member heterocyclic ring system optionally containing an additional heteroatom selected from O, S, and N—C1-4 alkyl, said heterocyclic ring system being optionally fused with a 5- to 6-member saturated, unsaturated or aromatic carbocyclic ring system or a 5- to 6-member saturated, unsaturated or aromatic heterocyclic ring system containing one to two heteroatoms selected from O, S, and N—C1-4 alkyl, wherein the fused ring system is unsubstituted or substituted with one to two substituents independently selected from hydroxyl, amino, fluoro, C1-4 alkyl, C1-4 alkoxy and trifluoromethyl; and
R3 and R4 are each independently H, C1-8 alkyl, C5-12 cycloalkyl, aryl, or aryl-C1-2 alkyl; or R3 and R4 together with the nitrogen atom to which they are attached form a C4-7 member heterocyclic ring system optionally containing an additional heteroatom selected from O, S, and N—C1-4 alkyl.
As disclosed in WO 03/004498, the Formula I compounds are important precursors for the synthesis of amide inhibitors of dipeptidyl peptidase-IV (general structure II), which are commercially available as drugs used to treat Type 2 diabetes (trade name, Sitagliptin, JANUVIA™)

As disclosed in WO 03/004498 and WO 04/087650, the amide inhibitors of dipeptidyl peptidase-IV are prepared by standard peptide coupling of a beta amino acid with fused heterocycles. However, a large number of synthetic steps required to prepare the beta amino acids, which make the processes unpractical.
Other routes (WO 2004/085661, WO 2004/085378 and WO 2006/081151) involve hydrogenation of enamine derivatives with a chiral auxiliary or asymmetric hydrogenation of an N-unprotected enamine in the presence of a rhodium catalyst and Joshiphos ligand. However, high catalyst loading or use of special solvents makes the processes not cost-efficient.
As disclosed in WO 2009/064476, the key intermediate beta amino acid was prepared via asymmetric hydrogenation of an N-Boc protected enamine with BINAP-RuCl2 as the catalyst. However, even with long reaction time (40 h) and elevated temperature (80° C.), 24.0% of the starting material was recovered. Furthermore, a low enantiomeric excess (ee) was afforded.
There remains a need for practical methods by which beta amino acids may be synthesized, especially those useful in the synthesis of amide inhibitors of dipeptidyl peptidase-IV.